A total of 613 patients were enrolled from six tertiary teaching hospitals in Korea. There were 367 (59.9%) boys and 246 (40.1%) girls, and the mean age was 3.49±5.17 years. Half of our patients (n= 311, 50.7%) were younger than 12 months. The mean number of episodes of infection was 1.2 (range, 1-5), and 17 (2.8%) patients experienced relapse of LFT elevation. The mean follow-up duration was 37.6±74.3 (range 1-486) days (Table 1). About one-third (n = 213, 34.7%) of the patients confirmed that they had one or more siblings and 121 (19.7%) patients had no siblings.
The mean values of LFTs were as follows; initial AST 171.2±274.1(range 23–2881) IU/L, initial ALT 194.9±316.1 (range 60–2949) IU/L, peak AST 198.1±300.6 (range 28–2881) IU/L, peak ALT 235.1±355 (range 60–2949) IU/L, final AST 60.6±49.5 (range 7–601) IU/L, and final ALT 72.5±77.4 (range 9–818) IU/L. However, the peak mean TB and DB were not elevated (Table 1). The PT/INR values were collected in 188 (30.7%) patients over the follow-up period and the median value was 1.07 (IQR 1.0–1.16). Five patients (0.82%) showed moderate coagulopathy (PT/INR > 1.5), including 2 with severe coagulopathy (0.33%, PT/INR > 2.0); however, none of them had other signs or symptoms of liver failure.
Infection focuses and pathogens
Respiratory infection was the most common diagnosis (n=276, 43.5%), followed by unspecified febrile illness (n=116, 18.3%), GI infection (n=111, 17.5%), and UTI (n=90, 14.2%) (Table 1). The mean follow-up duration was longest in CMV infection (133.6±91.2 days, range 21~255 days) following UTI (48.4±86.3 days, range 1~383 days) and GI infection (39.5±78.0 days, range 1~477days). In microbiologic and serologic studies, 385 pathogens were identified; however, laboratory evidence of specific pathogens could not be identified in 291 subjects (47.5%). Among the 322 microbiologic/serologic study-positive cases, 56 children (17.4%) had positive results for more than one pathogen. Rhinovirus was the most commonly identified pathogen (n=60, 9.8%), followed by respiratory syncytial virus (n = 57, 9.3%), Escherichia coli (n = 55, 9%), EBV (n= 46, 7.5%), and adenovirus (n=30, 4.9%) (Table 2). Regarding the median follow-up duration according to the known specific pathogen, CMV infection showed the longest duration (median 53 days, IQR 12.5–160 days), followed by norovirus (median 32 days, IQR 4–63 days) and parainfluenza virus (median 14.5 days, IQR 1–60.5 days) (Table 2).
Comparison between follow-up or follow-up loss groups
Although most patients (n=442, 72.1%) visited more than twice, approximately a quarter (n=171, 27.9%) of the patients did not (Table 3). The mean follow-up duration of the follow up group was 50.9±80.9 (range 2-486) days. Among those who failed to follow-up, the follow-ups of 108 (23.5%) patients were discontinued by physicians. (by non-GI pediatricians (n=60), pediatric gastroenterologists (n=8), pediatric residents (n=2) and emergency doctors (n=38)).
Follow-up rates and loss rates differed significantly among the attending doctors (p<0.001). Better compliance was observed in non-GI pediatricians and pediatric gastroenterologists (follow-up rates were 76.4% and 90.5%, respectively). However, the patients of pediatric residents and emergency doctors showed much poorer compliance; the follow-up loss rates were as high as 77.8% and 85.7%, respectively. Mean initial AST, ALT, and TB levels were significantly higher in the follow-up group (Table 3).
Factors related to ALT recovery
According to the univariate analysis, many variables were related to ALT recovery, such as number of infections, relapse, initial AST, ALT, TB, peak AST, ALT, and TB. However, after multivariate analysis, older age was associated with better ALT recovery (odds ratio (OR) of age for month was 1.003, p =0.004), while the number of infection episodes (OR =0.626, p <0.001) was associated with poor ALT recovery. We also observed that higher initial ALT and TB were related to poor prognosis, although they were not statistically significant (OR=0.999, OR=0.791, p=0.12, and p=0.08, respectively). Regarding clinical diagnosis, respiratory infection, UTI, and EBV infection were related to unfavorable prognosis for ALT recovery (Figure 1).
Abdominal sonography was the most commonly used diagnostic tool for hepatitis (n=226, 36.9%), while abdominal computed tomography (CT) was rarely used (n=17, 2.8%). Hepatotropic viruses including hepatitis B (n=190, 31%), hepatitis A (n=161, 26%), and hepatitis C (n=148, 24.1%) were usually screened. The other infectious markers used for hepatitis workup included EBV (n=139, 22.7%), CMV (n=99, 16.2%), HSV (n=68, 11.19%), rubella (n=45, 7.3%), and toxoplasma (n=41, 6.7%). In terms of metabolic and autoimmune screening tests, neonatal screening tests (n=10, 1.6%), serum amino acids (n=10, 1.6%), urine organic acids (n=11, 1.6%), ceruloplasmin (n=62, 10.1%), and FANA (n =50, 8.2%) were evaluated.
Pediatric gastroenterologists more frequently used diverse diagnostic modalities than non-GI pediatricians: abdominal sonography (57.9% vs. 34.9%), and antibodies against hepatitis B (50.0% vs. 28.9%), hepatitis A (42.1% vs. 25.1%), hepatitis C (40.5% vs. 21.4%), ceruloplasmin (28.6% vs. 5.8%), and FANA (20.6% vs. 5.5%) (Figure 2A). Less than 20% of emergency doctors and pediatric residents also performed diagnostic hepatitis workup. In addition to the difference among physicians for hepatitis workup, hospital-specific differences were also observed among tertiary hospitals in Korea (Figure 2B). These differences among physicians were statistically significant (p < 0.05), except for abdominal CT.